Use of extracts from pelargonium species

ABSTRACT

The present invention relates to the use of extracts from  Pelargonium  species or plant parts thereof, particularly from  P. sidoides  and  P. reniforme  for the prophylaxis or treatment of disease-related behavioural changes, the chronic or post-viral asthenia syndrome and/or stress-induced chronic pathological conditions as well as pharmaceutical preparations containing these extracts.

The present invention relates to the use of extracts from Pelargoniumspecies or plant parts thereof, particularly from P. sidoides and P.reniforme for the prophylaxis or treatment of disease-relatedbehavioural changes, chronic or post-viral asthenia syndrome and/orstress-induced chronic pathological conditions, as well aspharmaceutical preparations containing these extracts.

Many patients know from their personal experience that infections andinflammations such as a cold, influenzal infections or infections of theupper respiratory tracts are accompanied by a plurality of unspecificand generalized disease symptoms. Besides phenomena such as fever andarticular or muscular pain, also behavioural changes are among them.Thus, episodes of depression, listlessness, feeling of weakness,fatigue, anergy, anorexia, social isolation, weakness of concentration,sleep disorders, anxiety, indifferentism or hyperalgesia often occur inconnection with infective diseases. In their totality, these symptomsand behavioural disorders are designated as “acute phase reaction”,“sickness behaviour” or “depression due to a generalized disease” (W.Kozak et al., Am. J. Physiol. 272, R1298-R1307 (1997); R. Dantzer, BrainBehav. Immun. 15, 7-24 (2001); K. W. Kelley et al., Brain Behav. Immun.17, p. 112-p. 118 (2003); A. H. Miller, Brain Behav. Immun. 17, p.132-p. 134 (2003)).

On a molecular level these symptoms are caused by an increased synthesisof proinflammatory cytokines such as interleukuin-1 (IL-1), IL-6, tumornecrosis factor-α (TNFα) or interferons (INF). These mediators, whichare produced in increased amounts after tissue damages, elicitbehavioural changes indirectly via afferent nerve tracts or directlyafter transfer into the brain. Although sickness behaviour clearlyappears mainly in cases of infectious diseases, it is also observed inconnection with injuries, traumata, tumor diseases or inflammatoryreactions such as autoimmune diseases (R. Dantzer, Brain Behav. Immun.15, 7-24 (2001)).

The importance of cytokines for the development of unspecific diseasesymptoms and behavioural changes was recognized for the first time inthe scope of clinical studies. It turned out that the administration of,for example, IL-2 or interferons to patients with tumor diseases,hepatitis or multiple sclerosis causes influenza-like symptoms andpsychiatric disorders (such as acute psychoses and serious depressions).Meanwhile, there is a plurality of indication that thecytokine-dependent mechanisms that contribute to disease-relatedbehavioural changes play an important role also in the pathogenesis ofdepressions (L. Capuron and R. Dantzer, Brain Behav. Immun. 17, p.119-p. 124 (2003)).

In test animals sickness behaviour can be caused by direct injection ofproinflammatory cytokines or by administration of a cytokine inducersuch as a lipopolysaccharide, which are constituents of the cell wallsof gram-negative bacteria. Like in human beings, typical symptoms inanimals are, inter alia, a reduced uptake of food and water, loss ofweight, reduced social interactions, decreasing sexual behaviour,limited kinesic and exploratory behaviour or also a lack of interest forsweetened drinks.

The pathophysiologic importance of sickness behaviour presumably lies inan adaption of the organism to the modified needs of a diseasedorganism. As a result, exhausting physical activities (such as foragingand sexual behaviour) are avoided and temperature losses are limited(for example by physical rest). Simultaneously, the temperatureproduction is increased, for example by trepidation. These behaviouralchanges in total shall ease the healing process for the body. However,this condition should only last until it is no longer necessary for thehealing process. A number of mechanisms is known actually, which limitthe biological effects of the proinflammatory cytokines such as theincreased synthesis of gluco-corticoids, IL-10 orα-melanocyte-stimulating hormone (R. Yirmiya, Current Opinion inPsychiatry 10, 470-476 (1997)). Perturbations of these regulativemechanisms may contribute to a continuation of the immunologic andneuronal processes and may lead to a misdirected adaption reaction whichmanifests as chronic weakness syndrome (burnout syndrome, chronicfatigue syndrome, chronic exhaustion syndrome) or as post-viral weaknesssyndrome (post-viral fatigue syndrome). Various stress-induced chronicdisease conditions such as the posttraumatic stress, syndrome,fibromyalgia or multiple chemical sensitivity syndrome (multiplechemical sensitivity, sick building syndrome, electrical allergy),exhibit very similar symptoms and many patients fulfil the diagnosticcriteria for one or more of these diseases. It is common to all of themthat they are elicited by a state of stress which is followed by alonger lasting pathological condition. The preliminary stress isobviously the elicitor for the cell-promoting “circulus vitiosus”. Itbecomes more and more evident that there are close relations between thenervous system, the immune system and the hormone system and that allthese conditions are caused by a stress-induced reduced responsivenessof the immune system against anti-inflammatory signals (M. L. Pall(2001), Med. Hypotheses 57, 139-145; G. E. Miller et al. (2002), HealthPsychol. 21, 531-541).

Due to their frequent and regular appearance, the symptoms of thesickness behaviour are often ignored by physicians. They are ratherconsidered to be unpleasant side effects of the actual disease process,which cannot be avoided. However, it is clear from the knowledgeobtained in recent years that the disease-related behavioural changesand the physiological reactions associated therewith (e.g. fever) are acomplex pathological condition in themselves.

The symptoms of sickness behaviour can elicit a severe psychologicalstrain in affected patients and impair the quality of life dramatically.In particular, the lethargic attitude associated therewith cansignificantly hamper the patient's cooperation in therapeutic measures,such as in case of tumor diseases, or challenge the overall success ofthe treatment. Furthermore, in cases of trivial diseases such as aninfluenzal infection, the degree of severity of the symptoms of thedisease-related behavioural changes is often not in due proportion tothe, actual physiological purpose of this defensive mechanism.

The elucidation of the molecular mechanisms of sickness behaviour hasled to new possible ways for a therapeutic intervention in recent years.Antidepressive agents have turned out to be suitable for the treatmentof the depressive component of disease-related behavioural changes.However, antidepressive agents develop their therapeutic effect after adelay of several days or weeks and additionally often induce severe sideeffects. Therefore, for acute or less severe diseases these medicamentsare hot suitable or are of limited suitability only. Furthermore,antidepressive agents do not exert any influence on the neurovegetativesymptoms of sickness behaviour such as physical Weakness, exhaustion oranorexia. Therefore, there is an urgent need for effective treatmentmethods against disease-related behavioural changes that exhibit limitedside effects.

Extracts from the roots of the Pelargonium species P. sidoides and P.reniforme, which are domiciled in South Africa, are widely used in theAfrican traditional medicine for the treatment of diarrhea,gastrointestinal complaints, dysmenorrhoea and liver diseases. However,the administration against respiratory tract diseases and, particularly,against tuberculosis of the lung is predominant. Since many years, alsoan extract from the roots of P. sidoides is distributed under the tradename Umckaloabo for the treatment of acute and chronic infections of theotorhinolaryngologic regions such as rhinopharyngitis, tonsillitis,sinusitis and bronchitis. The clinical efficacy of this extract appearsto rely on antimicrobial and immuno-modulating effects. There areevidences from experimental investigations that an extract fromPelargonium sidoides increases the synthesis of TNF-α, INF-β and nitricoxide. (NO) (H. Kolodziej et al., Phytomedicine 10 (Suppl. 4), 18-24(2003)).

It now has been surprisingly observed that extracts from Pelargoniumspositively influence LPS-induced behavioural changes in animalexperiments despite the stimulating effect on the synthesis ofproinflammatory cytokines and, thus, can be employed for the prophylaxisand therapy of disease-related behavioural changes (“sicknessbehaviour”) in human beings and animals. Examples for thedisease-related behavioural changes are symptoms such as episodes ofdepression, listlessness, feeling of weakness, fatigue, anergy,anorexia, social isolation, weakness of concentration, sleep disorders,anxiety, indifferentism or hyperalgesia, which occur in a temporalcorrelation with infectious diseases, injuries, traumata, tumordiseases, inflammatory reactions or autoimmune diseases. Furthermore,the extracts are suitable for the prophylaxis and treatment of sicknessbehaviour in connection with the therapeutic application of natural orrecombinant cytokines such as interleukins, interferons and the like oralso with the application of cytostatic agents or other cell ortissue-damaging medicaments or therapeutic measures. Moreover,Pelargonium extracts can also be used for the prophylaxis and therapy ofthe chronic or post-viral asthenia syndrome (chronic or post-viralfatigue syndrome) and various stress-induced chronic pathologicalconditions such as the posttraumatic stress syndrome, fibromyalgia ormultiple chemical sensitivity.

Extracts from Pelargoniums or plant parts thereof can be obtainedaccording to known production methods in various compositions usingsolvents such as water, methanol, ethanol, acetone and the like as wellas mixtures thereof at temperatures from room temperature to 60° C.under slight to vigorous mixing or by percolation within 10 minutes to24 hours. Preferred extraction solvents for this purpose are mixtures ofethanol and water, particularly preferred in a ratio ethanol/water=10/90to 12/88 (w/w). In order to concentrate the active ingredients, furtherconcentration steps can be carried out, such as liquid-liquiddistribution using, for example, 1-butanol/water or ethylacetate/water,adsorption-desorption using ion exchangers, LH20, HP20. and other resinsor chromatographic separations using RP18, silica gel and the like Ifdesired, further processing to obtain dry extracts is carried outaccording to methods known per se by removing the solvent at anincreased temperature and/or reduced pressure or by freeze-drying.

The extracts according to the invention can be administered, preferablyorally, in form of powders, granules, tablets, dragées (coated tablets)or capsules or as a solution such as that directly obtained by theextraction.

For the preparation of tablets, the extract is mixed with suitablepharmaceutically acceptable adjuvants such as lactose, cellulose,silicon dioxide, croscarmellose and magnesium stearate and pressed intotablets which are optionally provided with a suitable coating made of,for example, hydroxymethylpropyl cellulose, polyethylene glycol,colorants (e.g. titanium dioxide, iron oxide) and talcum.

The extracts according to the invention can also be filled intocapsules, optionally after adding adjuvants such as stabilizers, fillersand the like. The dosage is such that 2 to 1000 mg, preferably 10 to 200mg extract are administered per day.

The efficacy of Pelargonium extracts against disease-related behaviouralchanges and/or chronic or post-viral asthenia syndrome are supported bythe experiments described below.

A dry extract from roots of P. sidoides, which was produced by means ofa double maceration using seven times their amount made up of 11 percentby weight ethanol at 55° C., respectively, (yield: 11%), was used forthe experiments. The extract was administered to male NMRI mice (20-25 gweight) by gavage in varying dosages in 0.2% agar suspension (10 ml/kg).Control animals received the agar suspension only. One hour after thetreatment, the animals were injected intraperitoneally with 400 μg/kglipopolysaccharide (LPS) (E. coli 0127:B8; Sigma, Deisenhofen) in 10mg/kg physiological saline (0.9% NaCl). After a further two hours, theanimals were transferred into the bright field of a dark-bright box andthe motility as well as the exploration behaviour were observed over aperiod of 3 minutes. As nocturnal animals, mice prefer to stay in a darksurrounding. Therefore, an extended stay in the bright region of thebright-dark box and a decreasing frequency of changes between the tworegions is to be assessed as an evidence for a reduced explorationbehaviour, anergy and reduced interest. The results of the experimentsare shown in the following table. It becomes evident that animalstreated with LPS stay significantly longer in the bright region comparedto control animals (NaCl) and change less often between the two regions.This effect is neutralized by the pre-treatment with the Pelargoniumextract in dose-dependant manner. TABLE Influence of Pelargonium extracton the exploration behaviour of mice in a bright-dark box. Stay in thebright Number of Dose region (seconds) changes of Substance mg/kg p.o.MW ± S.D. the region agar + NaCl 83 ± 8 8.5 ± 2.8 agar + LPS 135 ± 344.4 ± 2.8 Pelargonium extract + LPS 100 119 ± 18 5.5 ± 0.8 Pelargoniumextract + LPS 200  104 ± 18* 5.5 ± 1.4 Pelargonium extract + LPS 400  97± 11*  7.5 ± 1.9**P < 0.05 (=probability of error), t-test

1-14. (canceled)
 15. A method for treating a subject suffering from orsusceptible to one or more of disease-related behavioural change,chronic or post-viral asthenia syndrome and/or stress-induced chronicpathological conditions, the method comprising administering to thesubject one or more extracts from Pelargonium species selected from P.sidoides and P. reniforme or plant parts thereof.
 16. The method ofclaim 15 wherein the plant parts are roots.
 17. The method of claim 15wherein the one or more extracts are is an aqueous-ethanolic extractfrom roots of Pelargonium sidoides and/or reniforme.
 18. The method ofclaim 15 wherein the subject is suffering from or susceptible to adisease-related behavioural change.
 19. The method of claim 15 whereinthe subject is suffering from or susceptible to a disease-relatedbehavioural change associated with symptoms of episodes of depression,listlessness, feeling of weakness, fatigue, anergy, anorexia, socialisolation, weakness of concentration, sleep disorders, anxiety,indifferentism and hyperalgesia, which occur in a temporal correlationwith infectious disease, injuries, traumata, tumor disease, inflammatoryreaction or autoimmune disease.
 20. The method of claim 15 wherein thesubject is suffering from or susceptible to a disease-relatedbehavioural change in connection with the therapeutic application of acytokine, or with the application of a cytostatic agent or other cell ortissue-damaging medicament or therapeutic measure.
 21. The method ofclaim 15 wherein the subject is suffering from or susceptible to astress-induced chronic pathological condition.
 22. The method of claim21 wherein the subject is suffering from post-traumatic stress syndrome,fibromyalgia or multiple chemical sensitivity.
 23. The method of claim15 wherein the subject is identified as suffering from one or more ofdisease-related behavioural change, chronic or post-viral astheniasyndrome and/or stress-induced chronic pathological conditions, and theone or more extracts are administered to the identified subject.
 24. Themethod of claim 15 wherein the subject is identified as susceptible toone or more of disease-related behavioural change, chronic or post-viralasthenia syndrome and/or stress-induced chronic pathological conditions,and the one or more extracts are administered to the identified subject.25. A medicament for the prophylaxis or treatment of disease-relatedbehavioural changes, chronic or post-viral asthenia syndrome and/orstress-induced chronic pathological conditions comprising an extractfrom Pelargonium species selected from P. sidoides and P. reniforme. 26.A pharmaceutical comprising comprising one or more extracts fromPelargonium species selected from P. sidoides and P. reniforme and oneor more suitable adjuvants.
 27. The pharmaceutical comprising of claim26 wherein the composition consists of one or more extracts fromPelargonium species selected from P. sidoides and P. reniforme and oneor more suitable adjuvants.
 28. The pharmaceutical composition whereinthe composition is in an oral administration form.